The research outlined in this proposal will examine interactions occurring between ethanol and the metabolic activation of chemical carcinogens in isolated perfused rat livers. This research will be directed at three major objectives. 1) The influence of chronic ethanol administration on the metabolism of benzo(a)pyrene and dimethylnitrosamine in perfused livers and in isolated microsomes will be determined. In these experiments, the nutritional state will also be varied, in order to establish rate-limiting steps for carcinogen activation in whole cells. 2) The influence of the acute addition of ethanol on carcinogen activation will be studied. Direct effects of ethanol on enzymes of mixed-function oxidation and conjugation will be differentiated from indirect effects caused by the metabolism of ethanol and subsequent interactions with other metabolic pathways involved in carcinogen metabolism. 3) The effects of the acute and chronic addition of carcinogens on ethanol metabolism will be assessed. Potential points of interactions will be determined and the mechanisms involved will be defined. The increased risk of cancer in heavy consumers of ethanol is recognized as a significant health problem. These studies will define molecular mechanisms by which ethanol may increase the risk of cancer from chemical carcinogens.